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Immunity. 2017 Aug 15;47(2):363-373.e5. doi: 10.1016/j.immuni.2017.07.016. Epub 2017 Aug 8.

Dendritic Cells but Not Macrophages Sense Tumor Mitochondrial DNA for Cross-priming through Signal Regulatory Protein α Signaling.

Author information

1
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
2
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
3
Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
4
Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
5
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
7
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. Electronic address: yang-xin.fu@utsouthwestern.edu.

Abstract

Inhibition of cytosolic DNA sensing represents a strategy that tumor cells use for immune evasion, but the underlying mechanisms are unclear. Here we have shown that CD47-signal regulatory protein α (SIRPα) axis dictates the fate of ingested DNA in DCs for immune evasion. Although macrophages were more potent in uptaking tumor DNA, increase of DNA sensing by blocking the interaction of SIRPα with CD47 preferentially occurred in dendritic cells (DCs) but not in macrophages. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) in the DC cytosol, contributing to type I interferon (IFN) production and antitumor adaptive immunity. Thus, our findings have demonstrated how tumor cells inhibit innate sensing in DCs and suggested that the CD47-SIRPα axis is critical for DC-driven antitumor immunity.

PMID:
28801234
PMCID:
PMC5564225
DOI:
10.1016/j.immuni.2017.07.016
[Indexed for MEDLINE]
Free PMC Article

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